Opposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function

Liad Hinden; Majdoleen Ahmad; Sharleen Hamad; Alina Nemirovski; Gergő Szanda; Sandra Glasmacher; Aviram Kogot-Levin; Rinat Abramovitch; Bernard Thorens; Jürg Gertsch; Gil Leibowitz; Joseph Tam

doi:10.1038/s41467-022-29124-8

Opposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function

Liad Hinden, Majdoleen Ahmad, Sharleen Hamad, Alina Nemirovski, Gergő Szanda, Sandra Glasmacher, Aviram Kogot-Levin, Rinat Abramovitch, Bernard Thorens, Jürg Gertsch, Gil Leibowitz, Joseph Tam^*

^*Corresponding author for this work

School of Pharmacy

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Activation of the cannabinoid-1 receptor (CB₁R) and the mammalian target of rapamycin complex 1 (mTORC1) in the renal proximal tubular cells (RPTCs) contributes to the development of diabetic kidney disease (DKD). However, the CB₁R/mTORC1 signaling axis in the kidney has not been described yet. We show here that hyperglycemia-induced endocannabinoid/CB₁R stimulation increased mTORC1 activity, enhancing the transcription of the facilitative glucose transporter 2 (GLUT2) and leading to the development of DKD in mice; this effect was ameliorated by specific RPTCs ablation of GLUT2. Conversely, CB₁R maintained the normal activity of mTORC1 by preventing the cellular excess of amino acids during normoglycemia. Our findings highlight a novel molecular mechanism by which the activation of mTORC1 in RPTCs is tightly controlled by CB₁R, either by enhancing the reabsorption of glucose and inducing kidney dysfunction in diabetes or by preventing amino acid uptake and maintaining normal kidney function in healthy conditions.

Original language	American English
Article number	1783
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-29124-8
State	Published - Dec 2022

Bibliographical note

Funding Information:
We would like to thank Prof. Boaz Tirosh for his critical advice on mTORC1 signaling, and Dr. Dinorah Barasch for her technical assistance in LC-MS/MS analysis. This work was supported by an ERC-2015-StG grant (#676841), an Israel Science Foundation (ISF) grant (#158/18), and a JDRF grant (1-INO-2022-1128-A-N) to J.T. The work of G.S. was supported by the National Research, Development and Innovation Office grant NKFI-6/FK_124038.

Publisher Copyright:
© 2022, The Author(s).

Keywords

Animals
Diabetic Nephropathies/pathology
Kidney/metabolism
Kidney Tubules, Proximal/metabolism
Mammals
Mechanistic Target of Rapamycin Complex 1/genetics
Mice
Receptor, Cannabinoid, CB1/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-022-29124-8

Cite this

Hinden, L., Ahmad, M., Hamad, S., Nemirovski, A., Szanda, G., Glasmacher, S., Kogot-Levin, A., Abramovitch, R., Thorens, B., Gertsch, J., Leibowitz, G., & Tam, J. (2022). Opposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function. Nature Communications, 13(1), Article 1783. https://doi.org/10.1038/s41467-022-29124-8

@article{9fcd782d5ed54243add24f511982a039,

title = "Opposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function",

abstract = "Activation of the cannabinoid-1 receptor (CB1R) and the mammalian target of rapamycin complex 1 (mTORC1) in the renal proximal tubular cells (RPTCs) contributes to the development of diabetic kidney disease (DKD). However, the CB1R/mTORC1 signaling axis in the kidney has not been described yet. We show here that hyperglycemia-induced endocannabinoid/CB1R stimulation increased mTORC1 activity, enhancing the transcription of the facilitative glucose transporter 2 (GLUT2) and leading to the development of DKD in mice; this effect was ameliorated by specific RPTCs ablation of GLUT2. Conversely, CB1R maintained the normal activity of mTORC1 by preventing the cellular excess of amino acids during normoglycemia. Our findings highlight a novel molecular mechanism by which the activation of mTORC1 in RPTCs is tightly controlled by CB1R, either by enhancing the reabsorption of glucose and inducing kidney dysfunction in diabetes or by preventing amino acid uptake and maintaining normal kidney function in healthy conditions.",

keywords = "Animals, Diabetic Nephropathies/pathology, Kidney/metabolism, Kidney Tubules, Proximal/metabolism, Mammals, Mechanistic Target of Rapamycin Complex 1/genetics, Mice, Receptor, Cannabinoid, CB1/genetics",

author = "Liad Hinden and Majdoleen Ahmad and Sharleen Hamad and Alina Nemirovski and Gerg{\H o} Szanda and Sandra Glasmacher and Aviram Kogot-Levin and Rinat Abramovitch and Bernard Thorens and J{\"u}rg Gertsch and Gil Leibowitz and Joseph Tam",

note = "Funding Information: We would like to thank Prof. Boaz Tirosh for his critical advice on mTORC1 signaling, and Dr. Dinorah Barasch for her technical assistance in LC-MS/MS analysis. This work was supported by an ERC-2015-StG grant (#676841), an Israel Science Foundation (ISF) grant (#158/18), and a JDRF grant (1-INO-2022-1128-A-N) to J.T. The work of G.S. was supported by the National Research, Development and Innovation Office grant NKFI-6/FK_124038. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-29124-8",

language = "American English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Opposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function

AU - Hinden, Liad

AU - Ahmad, Majdoleen

AU - Hamad, Sharleen

AU - Nemirovski, Alina

AU - Szanda, Gergő

AU - Glasmacher, Sandra

AU - Kogot-Levin, Aviram

AU - Abramovitch, Rinat

AU - Thorens, Bernard

AU - Gertsch, Jürg

AU - Leibowitz, Gil

AU - Tam, Joseph

N1 - Funding Information: We would like to thank Prof. Boaz Tirosh for his critical advice on mTORC1 signaling, and Dr. Dinorah Barasch for her technical assistance in LC-MS/MS analysis. This work was supported by an ERC-2015-StG grant (#676841), an Israel Science Foundation (ISF) grant (#158/18), and a JDRF grant (1-INO-2022-1128-A-N) to J.T. The work of G.S. was supported by the National Research, Development and Innovation Office grant NKFI-6/FK_124038. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Activation of the cannabinoid-1 receptor (CB1R) and the mammalian target of rapamycin complex 1 (mTORC1) in the renal proximal tubular cells (RPTCs) contributes to the development of diabetic kidney disease (DKD). However, the CB1R/mTORC1 signaling axis in the kidney has not been described yet. We show here that hyperglycemia-induced endocannabinoid/CB1R stimulation increased mTORC1 activity, enhancing the transcription of the facilitative glucose transporter 2 (GLUT2) and leading to the development of DKD in mice; this effect was ameliorated by specific RPTCs ablation of GLUT2. Conversely, CB1R maintained the normal activity of mTORC1 by preventing the cellular excess of amino acids during normoglycemia. Our findings highlight a novel molecular mechanism by which the activation of mTORC1 in RPTCs is tightly controlled by CB1R, either by enhancing the reabsorption of glucose and inducing kidney dysfunction in diabetes or by preventing amino acid uptake and maintaining normal kidney function in healthy conditions.

AB - Activation of the cannabinoid-1 receptor (CB1R) and the mammalian target of rapamycin complex 1 (mTORC1) in the renal proximal tubular cells (RPTCs) contributes to the development of diabetic kidney disease (DKD). However, the CB1R/mTORC1 signaling axis in the kidney has not been described yet. We show here that hyperglycemia-induced endocannabinoid/CB1R stimulation increased mTORC1 activity, enhancing the transcription of the facilitative glucose transporter 2 (GLUT2) and leading to the development of DKD in mice; this effect was ameliorated by specific RPTCs ablation of GLUT2. Conversely, CB1R maintained the normal activity of mTORC1 by preventing the cellular excess of amino acids during normoglycemia. Our findings highlight a novel molecular mechanism by which the activation of mTORC1 in RPTCs is tightly controlled by CB1R, either by enhancing the reabsorption of glucose and inducing kidney dysfunction in diabetes or by preventing amino acid uptake and maintaining normal kidney function in healthy conditions.

KW - Animals

KW - Diabetic Nephropathies/pathology

KW - Kidney/metabolism

KW - Kidney Tubules, Proximal/metabolism

KW - Mammals

KW - Mechanistic Target of Rapamycin Complex 1/genetics

KW - Mice

KW - Receptor, Cannabinoid, CB1/genetics

UR - http://www.scopus.com/inward/record.url?scp=85127520822&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-29124-8

DO - 10.1038/s41467-022-29124-8

M3 - Article

C2 - 35379807

AN - SCOPUS:85127520822

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1783

ER -

Opposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this